A major goal of this AADCRC proposal is to understand how the innate and adaptive immune responses[unreadable] contribute to asthma In this Project, we concentrate on the innate response of airway epithelial cells and the[unreadable] special role of Stat1 signaling. We particularly develop the hypothesis that epithelial Statl signaling is a[unreadable] critical early step in defense against respiratory viruses and can thereby also regulate virus-inducible asthma[unreadable] traits in the short and long terms. Thus, loss of epithelial (versus immune) cell function for Stat1 is associated[unreadable] with exquisite sensitivity to respiratory viral infection. In the case of Sendai virus (SeV) infection, loss of Stat1[unreadable] gives rise to severe neutrophilic inflammation in mice that resembles severe RSV bronchiolitis in infancy. In[unreadable] the case of hMPV infection, loss of Stat1 allows for a striking eosinophilic inflammation and mucous cell[unreadable] metaplasia that may resemble hMPV infection in children with associated asthma symptoms. In contrast to[unreadable] Statl deficiency, a modification of Statl (designated Stat1-CC) that increases IFN responsiveness can[unreadable] increase viral clearance and improve outcome from infection. In the case of SeV, infection also causes[unreadable] delayed but then permanent switch to asthma traits (i.e., airway hyperreactivity and mucous cell metaplasia),[unreadable] and Stat1-CC protects against this long-term consequence as well. Moreover, these benefits appear[unreadable] achievable even when Stat1-CC expression is restricted to ciliated airway epithelial cells, the predominant[unreadable] site of viral replication. We therefore submit that epithelial Stat1 signaling is the first line of defense against[unreadable] infection by asthmagenic viruses and that compromise of this defense leads to more severe infection and in[unreadable] turn to a greater likelihood of developing acute and chronic asthmatic phenotypes. By contrast, we propose[unreadable] that modifying this epithelial system to enhance IFN efficacy can decrease the severity of viral infection and[unreadable] the likelihood of developing an asthmatic response. Thus, a proper balance of the Stat1 system is required to[unreadable] optimize host defense and minimize airway inflammation. To further develop this concept, we aim to: (i)[unreadable] Define the role of epithelial Stat1 signaling in acute and chronic responses to viral infection in a mouse[unreadable] model that focuses on the epithelial requirement for endogenous Stat1 as well as the benefit of epithelial[unreadable] Statl-CC in defense against infection with SeV and hMPV and the subsequent development of asthma traits,[unreadable] (ii) Define the role of epithelial Stat1 signaling after virus-induced wheezing in early childhood and after[unreadable] established asthma in adulthood. This aim will prospectively characterize the acute and chronic response to[unreadable] hMPV infection in children and the behavior of epithelial Stat1 signaling in this setting and will re-visit the[unreadable] issue of epithelial Stat1 signaling in adult asthma with attention to Stat1/Stat2 activation of type I IFN[unreadable] signaling. This Project will also collaborate with Project 2 and 3 in studies of complement component and[unreadable] inhibitory receptor signaling in T cells to gain a more complete analysis of the antiviral response and how it[unreadable] relates to the development of asthma.